Adoptive T cell therapy, which involves the reinfusion of expanded populations of tumor-specific T cells that have been isolated or engineered ex vivo, has achieved dramatic antitumor responses in a subset of patients with advanced melanoma and leukemia. However, only small subsets of patients have benefited from adoptive T cell therapy, in part because of the difficulty identifying and expanding high avidity tumor-reactive T cells from patients, and of maintaining the number and anti-tumor activity of the T cells in the patient after adoptive transfer. The introduction of tumor-targeting receptors into T cells by gene transfer to confer tumor reactivity provides a promising approach to overcome the obstacle of having to isolate tumor-reactive T cells from each patient to treat their malignancy, but does not solve the problem that the duration of in vivo survival of antigen-specific T cells that have been numerically expanded by culture ex vivo and adoptively transferred to patients is unpredictable, and often short. Thus, the identification of characteristics of T cells that determine their capacity to persist after transfer, and strategies to enhance survival and/or to expand transferred T cells in vivo that can be applied to humans could improve therapeutic outcome. Studies supported by this grant have utilized a nonhuman primate (NHP) model to address this important impediment to adoptive T cell therapy. This work has identified heritable qualities of TE cells that determine their fate in vivo and ability to establish durable T cell memory, and identified a role for interleukin 15 (IL-15) for supporting the long-term persistence of transferred T cells. The techniques used in the NHP model recapitulate those used in human adoptive therapy, and findings from this model are being translated into clinical trials of T cell therapy for cancer. The studies in this competing renewal will utilize the model to optimize strategies for administering IL-15 and for vaccination with a cellular vaccine comprised of an activated T cell that displays the cognate antigen, to enhance the magnitude and durability of T cell immunity achieved by adoptive transfer of TE cells, and evaluate the safety of targeting a novel molecule that is selectively expressed on human B cell malignancies. These studies have been selected for their immediate relevance and potential for rapid translation to human adoptive T cell therapy. The specific aims are: 1. To determine the safety and efficacy of subcutaneous IL-15 for improving the survival of adoptively transferred TE cells and their conversion to memory cells. 2. To optimize the use of systemic vaccination with T-cell antigen presenting cells (T-APC) for driving the in vivo expansion of adoptively transferred TE cells. 3. To determine the safety of adoptively transferring TE cells genetically modified to express a chimeric antigen receptor specific for ROR1, a surface molecule expressed on human B-CLL and mantle cell lymphoma, and conserved in M. mullata.